GPCRs: Dawn of a New Era?

Chapter 1
INTRODUCTION: THE UNTAPPED PHARMACOLOGIC POTENTIAL OF GPCRS
1.1. Research Advances Stimulating GPCR-Based Drug Discovery
1.2. Goals and Organization of Report

Chapter 2
SCIENTIFIC BACKGROUND AND TECHNOLOGIES
2.1. Nature of GPCRs
GPCRs as Drug Targets
GPCR Classification
2.2. Compound Selection
Functional Assays for GPCR Signaling
Calcium Assays
Cellular Dielectric Spectroscopy
Beta-Arrestin Assays
Structure-Based Drug Discovery

Chapter 3
GPCR PHARMACOLOGY: KEY ADVANCES IN BASIC RESEARCH
3.1. Significance of GPCR Structures
X-Ray Crystallographic Structure of the Beta2-Adrenergic Receptor…Solved
Implications for Structure-Based Drug Design for GPCRs
3.2. Deorphanization
3.3. Allosteric Modulators
3.4. Dimers and Oligomers
3.5. Functional Selectivity

Chapter 4
APPLIED RESEARCH
4.1. Small Companies Push the Limits of GPCR Pharmacology
7TM Pharma
Acadia Pharmaceuticals
Actelion
AcurePharma
Addex Pharmaceuticals
Adenosine Therapeutics (Acquired by Clinical Data)
Arena Pharmaceuticals
Cara Therapeutics
Dimerix Bioscience
EPIX Pharmaceuticals
Trevena
4.2. The GPCR Pipeline
Serotonin Receptors
5-HT1 Receptor
5-HT2 Receptor
5-HT4 to 5-HT7 Receptors
Adenosine Receptors
A1 Receptor
A2 and A3 Receptors
Adrenergic Receptors
Alpha Adrenergic Receptor
Beta Adrenergic Receptor
Angiotensin II Receptor
Arginine Vasopressin Receptor
Bradykinin Receptors
Calcitonin Receptors
Cannabinoid Receptor
Chemokine Receptors
Cholecystokinin Receptor
Muscarinic Acetylcholine Receptor
Coagulation Factor II Receptor
Corticotropin-Releasing Hormone Receptor 1
Dopamine Receptors
Endothelin Receptor Type A
GABAB Receptor
Glucagon Receptor Family
Metabotropic Glutamate Receptors
Gonadotropin-Releasing Hormone Receptor
Ghrelin Receptor
Histamine Receptor
Interleukin 8 Receptor
Melanin-Concentrating Hormone Receptor 1
Melanocortin Receptor
Motilin Receptor
Opiate Receptor-Like 1 and Opioid Receptors
Oxytocin Receptor
Prostaglandin Receptors
GPCR44
Purinergic P2Y Receptors
Sphingosine-1-Phosphate Receptor 1
Tachykinin Receptors
Additional GPCR Modulators

Chapter 5
DEALS, OBSERVATIONS, AND CONCLUSIONS
5.1. Selected GPCR-Related Deals
5.2. Strengths and Weaknesses of GPCRs as a Target Class
Strengths
Weaknesses
5.3. General Observations and Findings
Diversity of GPCRs for Drug Discovery and Development
Translation of Basic Research and New Technologies
Functional Versus Ligand-Binding Screening Assays
Cell Impedance Screening Technology
Role of Allostery in Drug Discovery and Development
Role of Dimers and Oligomers in Drug Discovery and Development
Relationship of Signaling Pathway to Disease
Deorphanization and Unfamiliar GPCRs
Structure-Based Drug Design
5.4. Conclusions

Chapter 6
EXPERT INTERVIEWS
6.1. Annette Gilchrist, PhD
Adjunct Professor; Northwestern University
6.2. Graeme Milligan, PhD
Professor of Molecular Pharmacology; Joint Research Director, Faculty of Biomedical and Life Sciences; University of Glasgow
6.3. Anonymous
Screening and Profiling Director; Major Pharmaceutical Company X
6.4. P. Jeffrey Conn, PhD
Lee E. Limbird Professor of Pharmacology; Director, Vanderbilt Program in Drug Discovery; Vanderbilt University Medical Center
6.5. Sidney Topiol, PhD
Associate Director, Computational Chemistry; Lundbeck Research
6.6. Vincent Mutel, PhD
CEO, Vice Chairman, and Co-Founder; Addex Pharmaceuticals

References
Company Index with Web Addresses

FIGURES
Figure 2.1. Diagram of a FLIPR Instrument and Typical Kinetic Tracings
Figure 2.2. Crystal Structure of the Beta2-Adrenergic Receptor Protein

TABLES
Table 2.1. Major GPCR Subclasses
Table 4.1. Launched Drugs Targeting Serotonin 1 Receptors
Table 4.2. Drug Candidates for Serotonin 1 Receptors
Table 4.3. Launched Drugs Targeting Serotonin 2 Receptors
Table 4.4. Drug Candidates for Serotonin 2 Receptors
Table 4.5. Launched Drugs Targeting Serotonin 4 Receptors
Table 4.6. Drug Candidates for Serotonin 4 Receptors
Table 4.7. Drug Candidates for Serotonin 5, 6, and 7 Receptors
Table 4.8. Drug Candidates for Adenosine A1 Receptors
Table 4.9. Drug Candidates for Adenosine A2 and A3 Receptors
Table 4.10. Launched Drugs Targeting Alpha Adrenergic Receptors
Table 4.11. Drug Candidates for Alpha Adrenergic Receptors
Table 4.12. Launched Drugs Targeting Beta-1 Adrenergic Receptors
Table 4.13. Drug Candidates for Beta-1 Adrenergic Receptors
Table 4.14. Launched Drugs Targeting Beta-2 Adrenergic Receptors
Table 4.15. Drug Candidates for Beta-2 Adrenergic Receptors
Table 4.16. Drug Candidates for Beta-3 Adrenergic Receptors
Table 4.17. Launched Drugs Targeting Angiotensin II Receptor, Type 1
Table 4.18. Drug Candidates for Arginine Vasopressin Receptors
Table 4.19. Drug Candidates for Bradykinin Receptors
Table 4.20. Drug Candidates for Calcitonin and Calcitonin-Like Receptors
Table 4.21. Preclinical Drug Candidates for Cannabinoid 1 Receptors
Table 4.22. Clinical Drug Candidates for Cannabinoid 1 Receptors
Table 4.23. Drug Candidates for Cannabinoid 2 Receptors
Table 4.24. Drug Candidates for Chemokine Receptors
Table 4.25. Drug Candidates for Cholecystokinin Receptors
Table 4.26. Launched Drugs Targeting Muscarinic Receptor 1
Table 4.27. Drug Candidates for Muscarinic 1 and 2 Cholinergic Receptors
Table 4.28. Launched Drugs Targeting Muscarinic Receptor 3
Table 4.29. Drug Candidates for Muscarinic 3 Cholinergic Receptors
Table 4.30. Drug Candidates for Coagulation Factor II Receptor
Table 4.31. Drug Candidates for Corticotropin-Releasing Hormone Receptors
Table 4.32. Launched Drugs Targeting the Dopamine D2 Receptor
Table 4.33. Drug Candidates for Dopamine Receptors
Table 4.34. Drug Candidates for Endothelin Receptor Type A
Table 4.35. Drug Candidates for GABAB Receptors
Table 4.36. Drug Candidates for Glucagon and Glucagon-Like Peptide-1 Receptors
Table 4.37. Drug Candidates for Metabotropic Glutamate Receptors
Table 4.38. Launched Drugs Targeting the Gonadotropin-Releasing Hormone Receptor
Table 4.39. Drug Candidates for the Gonadotropin-Releasing Hormone Receptor
Table 4.40. Drug Candidates for Ghrelin (aka Growth Hormone Secretagogue) Receptors
Table 4.41. Launched Drugs Targeting the Histamine H1 and H2 Receptors
Table 4.42. Drug Candidates for Histamine Receptors
Table 4.43. Drug Candidates for Interleukin 8 Receptors
Table 4.44. Drug Candidates for Melanin-Concentrating Hormone Receptor 1
Table 4.45. Drug Candidates for Melanocortin Receptors
Table 4.46. Drug Candidates for the Motilin Receptor
Table 4.47. Drug Candidates for Opiate Receptor-Like 1; Also for Delta 1 and Kappa 1 Opioid Receptors
Table 4.48. Drug Candidates for Opioid Receptors Mu and Sigma
Table 4.49. Drug Candidates for the Oxytocin Receptor
Table 4.50. Launched Drugs Targeting Prostaglandin Receptors
Table 4.51. Drug Candidates for Prostaglandin Receptors
Table 4.52. Drug Candidates for GPCR 44
Table 4.53. Drug Candidates for Purinergic Receptors
Table 4.54. Drug Candidates for Sphingosine-1-Phosphate Receptor 1
Table 4.55. Drug Candidates for Tachykinin Receptors
Table 4.56. Launched Drugs Targeting Miscellaneous GPCRs
Table 4.57. Miscellaneous GPCR-Targeted Drugs in Development
Table 5.1. Selected Recent GPCR Candidate–Compound-Related Deals